The goal of this Phase II competing renewal application is to complete the preclinical development of a remarkable small-molecule inhibitor of the Ca2????dependent phosphodiesterase 1B (PDE1B) - IC041. This program builds upon our currently- funded Phase II in which we proposed to discover small molecule PDE1 inhibitors suitable for use as an antidepressant medication. As a result of our Phase II research we have successfully discovered a IC041 (and a portfolio of PDE1 inhibitors) with remarkable potency (i.e., sub-nanomolar) and selectivity (>1000-fold selective). IC041 has pro-cognitive effects, as measured by significant effects in both rats and mice in the Novel Object Recognition (NOR) task. While continuing to evaluate PDE 1 inhibitors for anti-depressant activity, we will develop the lead pre-clinical candidate - IC041 - for the treatment of cognitive dysfunction in schizophrenia. This application includes plans to complete pre-clinical studies necessary to enable an Investigational New Drug (IND) application for our lead compound for treatment of cognitive dysfunction in schizophrenia. Medicinal chemistry and efficacy will be preformed in order to identify other potent and orally-available back-up compounds. Three Specific Aims are proposed: to complete IND-enabling GLP Safety and Toxicology studies of our lead compound, IC041, in two species; to perform medicinal chemistry to identify up to three promising back-up compounds to IC041; and to evaluate up to three promising back-up compounds to IC041 for behavioral efficacy in rodent models of cognition and motivation. PUBLIC HEALTH RELEVANCE: According to the NIMH initiative titled "Measurement and Treatment Research to Improve Cognition in Schizophrenia" (MATRICS), " ...cognitive deficits affect nearly every individual with schizophrenia. Moreover, the severity of these cognitive deficits is closely related to the severity of functional impairments that result in poor community adaptation and work disability for the large majority of individuals affected by this illness." In this proposal Intra-Cellular Therapies, Inc. (ITI) seeks to develop a novel drug that will positively impact brain pathways involved in cognition that have been implicated in cognitive dysfunction in schizophrenia. We will develop agents that can be safely co-administered with existing antipsychotics that may provide a significant improvement in this so-far untreated symptom of the disease. [unreadable] [unreadable] [unreadable]